1. Is It Time To Replace Ovarian Stimulation in IVF With Alternatives
Dr. Milton Leong
MDCM DSc (McGill)
Director, IVF Center, HKSH
Specialist in Reproductive Medicine
Adjunct Professor, OBS-GYN, McGill University

2. The first IVF Baby
Drs. Steptoe and Edwards decided to abandon the use of fertility medications and try aspirating a single egg in a natural menstrual cycle. On their second attempt, Louise Brown was conceived

3. Ovarian Stimulation for IVF
Natural Cycles
Clomiphene, Clomiphene/HMG
HMG
FSH stimulation with agonists
FSH stimulation with antagonists

4. Ovulation Stimulation
WHAT GOES AROUND COMES AROUND
*American idiom

5. Stimulated ovary

6. Technology and product development timeline: gonadotrophins
Horse PMSG
Pig
FSH
Pituitary
FSH
u-hMG
u-FSH u-FSH r-hFSH
(HP)
r-hFSH FbM
Consistency
Quality
Local reactions
Potential side-effects
Antibodies
Creutzfeldt–Jacob disease
Local, systemic reactions
Adapted from: Lunenfeld. Reprod Biomed Online 2002;4:11

7. Premature LH surge Poor quality
No fertilization or very poor pregnancy rate
Cancel egg retrieval
5-20%
5-20%
All cycles treated in early 1980’s

8. I Review “Gold Standard” Discuss Alternatives
Introduce Concept of Preparing Ovary for Egg Collection in IVF

9. GnRHa Long Protocol vs No Suppression meta-analysis IVF cases
Odds ratios for IVF clinical pregnancy after GnRH-a versus clomiphene/FSH/hMG ovulation induction protocols

10. Results of first application of GnRH-agonists in the long protocol
11 patients eligible for IVF
GnRH agonists s.c. (busereline) started at day of menstruation of one day before
Ovarian stimulation started with HMG or purified FSH when all ovarian follicles and the endometrial lining has disappeared on ultrasound (average 15 days)
One ongoing pregnancy achieved
Porter RN, Smith W., Craft IL., Abdulwahid NA., JAcobs HS (1984) Induction of ovulation for in-vitro fertilization using buserelin and gonadotropins. Lancet 2;
Porter et al., 1984

11. OVARIAN STIMULATION FSH with agonist down regulation
FSH with antagonists
Low dose clomid/FSH stimulation
Delayed stimulation
IVM
Natural cycles

12. Structure of GnRH agonists
Modifications of natural GnRH
to have GnRH agonistic properties 1 2 4 3 6 5 9 8 10 7
pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
activation of the
GnRH receptor
regulation
of GnRH
receptor
affinity
regulation of
biologic activity
Modification of position 6 and 10 is typical for all GnRH agonists. This leads to a change in
- GnRH receptor affinity (which is increased)
- regulation of biologic activity (which is increased due to a longer half life)

13. Individualizing protocols
Our contribution to
1. low dose short term agonist down regulation using decapeptyl
2. flexible low dose antagonist
Aims: - to simplify treatment
- to minimize drug usage

14. Decapeptyl Down Regulation 2000-2002
Total
< 40
≥ 40
# of patients 90
76 (32.9)
14(40.8)
# of pregnancy 42 40 2
Pregnancy %
46.7
52.6 14
# of twins+ 10
# of babies 43 1
Miscarriage rate
16%
50%

15. Decapeptyl Down Regulation 2000-2003 Laboratory Data
# of eggs
831
MTII 539 (67%)
MTI 139 (16.7%)
# of eggs ICSI
551
# of fertilized
427
Fert. % 76.4
# of E.T.
244
Mean transferred 2.7
# of preg. (F.H.) 46
Implantation rate 21%

16. Agonist Studies 2000 - 2001 Deca Long Luc Long Bus <40
Number of OPU 69 76 61
Number of Eggs Retrieved
881
885
726
Number of MTII
647, 73%
642, 73%
552, 76%
Number of MTI
136, 15%
44, 5%
101, 14%
Fertilization Rate
74%
76%
71%
Mean # of Embryos Transferred per ET
3.1
3.2
2.8
Pregnancy Rate per ET
51%
49%
44%
Implantation Rate
20%
22%
18%
Average Age
34.4
33.2
34.9

17. Down Regulation

18. GnRH agonists Undesirable effects: Over-suppression: Also it is:
LH becomes so low that it affects the production of estrogen, and possibly progesterone in the luteal phase
Leads to poor response, poor pregnancy outcome due to early abortion.
Also it is:
Too long and too much drug use, cost, cancelled cycles and it is unnatural.

19. Structure of GnRH antagonists
to achieve antagonistic properties of natural GnRH more
modifications than only in position 6 and 10 are necessary 1 2 4 3 6 5 9 8 10 7
pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
activation of the
GnRH receptor
regulation
of GnRH
receptor
affinity
regulation of
biologic activity
In contrast to GnRH agonists, there are more changes necessary in the structure of the natural GnRH molecule, to achieve antagonistic properties. These antagonistic properties mean:
- no intrinsic effect
- competitive action

20. Comparison: Mode of Actions
Antagonists
Agonists
Immediate onset of actions (shortens treatment durations)
Prevents hormonal withdrawal symptoms
No recovery time of the pituitary
long pre-treatment
Hormonal (estrogen) withdrawal symptoms through desensitization of pituitary
Recovery of the pituitary gonadotrophin secretion, after stopping the treatment takes about 2 weeks.

21. Cetrorelix 0.125mg Flexible Dose Trial
Selection Criteria:
1. Previous over-suppression with agonist
2. Previous poor response
3. Previous LH surge if no agonist

22. BMI Distribution
Mean = 21.8 (range 19-30)
Mean = 21.8 (range 19-30)

23. # Days Cetrorelix Used
Mean = 2.2 days (range 1-3)

24. LH and Cetrorelix 0.125mg/day
Range mIU/ml
Pre
Day 1 post
Day HCG

25. Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006 0.125 mg/day
Cycles
121
331
Average age
37.1±4.0
37.5±4.2 NS
Days of stimulation
9.3±1.7
9.4±1.8
Total dose of FSH used (amp)
31.4±14.4
36.0±14.5
0.004
E2 on HCG day (pg/ml)
1943±941.8
2028.0±1376.0
LH on HCG day (IU/L)
3.5±3.9
2.1±1.9
0.001
Oocytes collected
1160 (9.6)
3198 (9.7)
MTII
902 (77.75%)
2503 (78.26)
Fertilized oocytes (fertilization rate)
770 (85.4%)
2085 (83.3%)
Embryos transferred
2.8±0.8
2.9±0.8
Pregnancy rate/ET
50/121 (41.3%)
106/331 (32.0%)
NS (P=0.066)
Implantation rate
17.3%
13.4%
NS (P=0.081)

26. Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006 (age <40)
0.125 mg/day
0.25 mg/day P
Cycles 86
215
Average age
35.1±3.1
35.2±2.9 NS
Days of stimulation
9.4±1.7
9.3±1.8
Total dose of FSH used (amp)
29.6±11.9
33.2±11.6
0.016
E2 on HCG day (pg/ml)
2081.5±977.6
2040.6±1300.2
LH on HCG day (IU/L)
3.7±4.4
2.1±1.8
0.002
Oocytes collected
941 (10.9)
2240 (10.4)
MTII
732 (77.78%)
1742 (77.76)
Fertilized oocytes (fertilization rate)
623 (85.1%)
1448 (83.1%)
Embryos transferred
2.8±0.6
2.8±0.7
Pregnancy rate/ET
43/86 (50.0%)
84/215 (39.1%)
NS (P=0.083)
Implantation rate
21.8%
17.4%
NS (P=0.144)

27. Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006 (age ≥40)
0.125 mg/day
0.25 mg/day P
Cycles 35
116
Average age
41.6±1.7
42.0±2.3 NS
Days of stimulation
9.1±1.8
9.4±1.9
Total dose of FSH used (amp)
36.0±18.6
41.1±17.7
E2 on HCG day (pg/ml)
1602.2±756.1
2003.9±1517.8
LH on HCG day (IU/L)
3.0±2.4
2.2±2.1
Oocytes collected
219 (6.26)
958 (8.25)
MTII
170 (77.6%)
761 (79.4%)
Fertilized oocytes (fertilization rate)
147 (86.5%)
637 (83.7%)
Embryos transferred
2.9±1.1
3.0±1.0
Pregnancy rate/ET
7/35 (20.0%)
22/116 (19.0%)
Implantation rate
6.9%
6.6%

28. The GnRH Antagonists Conclusions:
Why treat 100% of patients when we are trying to prevent 5-10% LH surge
Avoid over-suppression and poor response
Effective in preventing LH surge
Reduction of hyper-stimulation
Lower costs

29. Antagonist vs Agonists
Cet
Agonist
<40
≥40
Number of OPU
371
184
171 23
Number of Eggs Retrieved
3994
1388
2126
199
Number of MTII
2984(75%)
1055(76%)
1575(74%)
152(76%)
Number of MTI
526 (13%)
160 (12%)
205 (10%)
25 (13%)
Number of ICSI’d
3269
1131
1729
173
Number of 2PN
2472
870
1303
126
Fertilization Rate
76%
77%
75%
73%
Total # of Embryos Transferred
1039
521
532 62
Mean # of Embryos Transferred per ET
2.8
3.1
2.7
Number of Pregnancy
145 25 82 5
Pregnancy Rate per ET
39%
14%
48%
22%
Implantation Rate
17% 5%
20%
10%
Average Age
35.1
41.8
33.7
41.5

30. Problems With Ovarian Stimulation
Cost
Physical Suffering
Immediate side effects
Future side effects
OHSS

31. Problems with Ovarian Stimulation
Drug Cost
Up to 40% of cost in IVF
30% of patients who would not choose IVF as fertility treatment cited cost as the deciding factor
(fertility survey by YWCA HK 2002)

32. In 2 surveys on the population’s perception of IVF, Europe 1996 and Hong Kong 1998, 50% of infertile couples know about IVF but will not undergo treatment.
The main reasons are: Religion, Cost, Worried about side effects of drugs

33. Problems with Ovarian Stimulation
Potential Cancer Risks:
Clomiphene use increased risks for Invasive and Borderline epithelial Ovarian tumors
Gravid RR
Nulligravid RR 27.0
Whittemore, Harris et al 1992

34. Problems With Ovarian Stimulation
OHSS
Up to 6% of all FSH stimulated IVF cycles
1.5% Severe
Compare NO OHSS with unstimulated cycles

35. Reduction of OHSS using Cetrotide
Multiple dose protocol
rate of OHSS: 6.5% vs. 1.1% (agonist vs. antagonist protocol)
RR 6.2, 95% CI: , p = 0.03
Single dose protocol
rate of OHSS: 11.1% vs. 3.5% (agonist vs. antagonist protocol) 95% CI: to 3.2
patients requiring hospitalisation: 5.6% vs. 1.8%
(agonist vs. antagonist protocol) 95% CI: to 4.1
With both Cetrotide protocols a clear reduction of OHSS was achieved

36. Problems with Ovarian Stimulation
Waste of Human Resources
Excess eggs ? how to deal with
Excess embryos - even worse
Multiple pregnancies and their associated complications

37. So it is time to
Individualise
More User Friendly Alternatives

38. New Mindset Don’t think STIMULATION
Think Preparing the Ovary for Egg Collection
Think Patient Orientated Treatment
Always Minimise Trauma to Patients

39. Ovum Preparation for IVF
FSH/GnRH Down Regulation
FSH/GnRH Antagonists
Clomid, Clomid/FSH
Minimal Stimulation
IVM
Natural Cycles

40. Preparation for Egg Collection
Routine IVF
Ovulation Stimulation
FSH
FSH with Agonist Down Regulation
FSH with Antagonists

41. Preparation for Egg Collection
Natural Cycle IVF
Minimal Stimulation IVF
In Vitro Maturation of eggs/IVF

42. We should stop thinking of Ovarian Stimulation, but start to consider, in all IVF cases, that we have to prepare the ovary for egg collection. Only if we do this, we can set our mind on how best we can serve our patients, in their interest and primarily in their interest.

43. Preparing the Ovary for Egg Collection for IVF
Group A
Young age
No medical problem or history
Previous Pregnancy
ANC >5
Consider No Stimulation

44. Preparing the Ovary for Egg Collection in IVF
Group B
PCO
Previous History of Poor Response
Raised Day 2 FSH
Consider IVM/IVF with/without stimulation

45. Preparing the Ovary for Egg Collection
Group C
No Contradiction to stimulation
No previous Adverse History
Normal Day 2 FSH
Normal Antral Follicle Count
Gold Standard: HMG/FSH
with Agonist/Antagonist

46. Over responders Risk of OHSS Treatment options Cancel cycle Coasting
No embryo transfer
Convert to IVM

47. Over responders Prolonged Coasting Aim: To prevent hyperstimulation
Practice: Coast till E2 ≤ 3000 pg/mL
Sher, 1995 Start when 30% follices > 15 mm
Nilsson, 1999 When 3 follicles > 17mm

48. Over Responders
A better choice is to convert over-responders, once recognised, to IVM. IN this case, OHSS can be avoided, and pregnancy maintained, as coasting cannot guarantee relief of OHSS, and sometimes oocyte quality is compromised

49. Over Responders

50. Poor responders Age (average age of ML patient 38.7 yrs)
Decrease ovarian reserve (↑D2 FSH)
Decrease antral follicles count
Previous ovarian surgery
(Laparoscopic ovarian cystectomy)

51. Poor responders High dose Microdose flare
Low dose clomid/FSH stimulation
Delayed stimulation
IVM

52. Poor Responders
Review of randomised control trials and retrospective studies showed that increasing the FSH dosage over 300U/day has no clinical benefit. The cost of treatment and side-effects were higher
Hamilton et al 2007

53. Minimal stimulation

54. Delayed Stimulation

55. Delayed Stimulation Including 10 cases converted to IUI
25 patients
Age
30-45
41.5
D2 FSH
U/L
15.2
FSH 150U/D (days)
3-10
4.2
#eggs
121
2.2
% Fert
93/121
76.9%
# Trans/Preg
74 (2.9)
4/25 (16%)
Impl%
4/74
5.4%

56. Poor responders High dose Microdose flare
Low dose clomid/FSH stimulation
Delayed stimulation
IVM

57. Stimulation in IVM No difference in laboratory data
No difference in clinical data
Makes ovum collection easier
In non-PCO patients who needs IVM
medical, psychological reasons
slow responding IVM patients
Makes IVM User Friendly

58. IVM stimulation

59. IVM results 2004 Aug to 2006 Dec <38 ≥38 Patients (n) 53 24
Average age
32.6
40.0
Total eggs
674 (12.7 )
166 (8.3)
MTII stage
504 (74.8%)
146 ( 76.9%)
Fertilization rate
408 (80.9%)
113 (87.0%)
Pregnancy rate
19/53 (35.8%)
8/24 (33.3%)
Embryos transferred
138 (2.6)
88 (3.7)
Implantation rate
23/160 (14.3%)
17.6%

60. IVM/IVF Selection Method

61. Natural Cycle IVM/IVF Maria Hospital Korea
Group1: Succeed to collect oocytes from Leading Follicle
Group2: Failed to collect ooyctes from Leading Follicle

62. Comparison of Outcomes in IVF/M, IVM and COH

63. Modern Trend in ART Minimize multiple pregnancies
Minimize number of embryos transfer
Minimize patients’ load and stress
Physiological
Psychological
Financial

64. Question
Is it time to revisit the aim and clinical practice of so called Controlled Ovarian Hyperstimulation. Should we be heading towards a modified direction

65. Answer
We should look at the clinical aim of “Preparing Eggs for the treatment of IVF” rather than Ovarian Stimulation

66. Preparation for Ovum Collection
Natural Cycles
Minimal stimulation (clomiphene/FSH)
IVM
FSH stimulation with agonists
FSH stimulation with antagonists

67. Conclusions:
It is possible to choose stimulation procotol according to: age
Ovarian status
Previous history
We should aim for minimal stress (in all senses) for the patients provided similar result can be obtained.
Individualization of stimulation should be considered for every case.